The present invention relates to microfabricated devices, and more particularly to microstructural particles for use in improving the bioavailability of protein, peptide and other pharmacologically active biopolymers delivered by the oral route.
Peptide- and protein-based therapeutic agents exhibit poor bioavailability after oral administration. This is due to poor absorption of such macromolecules across the mucosal surfaces of the stomach, intestine and colon. Moreover, peptidase enzymes found in abundance in the gastrointestinal (GI) tract destroy many peptide and protein drug before they have an opportunity to be absorbed. A variety of delivery systems have been devised to improve the oral bioavailability of drugs including, enterically-coated tablets (including osmotic pumps), capsules, and particles, liposomes, micro- and nanoparticles composed of biodegradable polymers such lactide-co-glycolides, microemulsions with surface active agents incorporated, biodegradable hydrogels, and the like. In many instances, the dosage forms incorporate penetration enhancers (also known as carriers). These agents include bile salts (as sodium salt such as sodium glycocholate), anionic detergents (such as docusate sodium and sodium lauryl sulfate), nonionic detergents (medium chain triglycerides, propylene glycol), salicylates, acyl amino acids, and acylcarnitine. Other enhancers are known to increase intestinal permeability through action on the tight junctions. An example of this type of agent is zonula occludens toxin (ZOT).
The invention includes, in one aspect, a particle for use in oral delivery of a biopolymeric drug such as a polypeptide, protein or polynucleic acid to a subject. The particle has a substrate having front and back faces, and defining at least one reservoir which opens to said front face. A biopolymer agent is contained in said at least one reservoir in releasable form. A muco-adhesive agent is carried on the substrate""s front face, for attaching the particle to the intestinal mucosal lining, so that drug released from the reservoir is presented directly to the region of intestinal lining at which the particle is attached.
The particle is preferably disc-shaped, has a diameter in the range of 100 xcexcm2 to 1 mm, and a particle density of 1.00xc2x10.05 gm/cm3.
Exemplary bio-polymeric agent include factor VII, erythropoietin, human growth hormone, various colony stimulating factors, such as GM-CSF, interferons, interleukins, vasopressin, growth hormone releasing factor, relaxin, somatostatin, antibodies, insulin, atrial naturetic factor, glucagon; desmopressin, calcotonin, various angiogenic growth factors, such as VEGF, LHRH analogs, peptide antigens, vaccines, and antisense oligonucleotides and oligonucleotide analogs. The muco-adhesive agent may be plant lectin, such as wheat germ agglutinin, tomato lectin, Ulex europaeus agglutinins I and II, Phaseolus vulgaris agglutinin, asparagus pea lectin (Lotus tetragonologus), Mycoplasma gallisepticum lectin, B-subunit of cholera toxin (CT), Escherichia coli type-1 fimbriae, vitamin B12, riboflavin, folate, or iron/transferrin, that binds to the intestinal mucosa. The agent may be mixed with an excipient to achieve a controlled rate of dissolution and release of the agent from the reservoir. One of the reservoirs may contain a permeation enhancer, and one may contain a peptidase inhibitor.
In another aspect, the invention includes a composition of the drug-delivery particles. The composition preferably contains an enteric-coating material that encapsulates the particles and which is effective, after oral delivery, to remain intact while passing through the low pH environment of the esophagus and stomach, and to dissolve in the higher pH environment of the intestinal lumen, releasing said particles.
In still another aspect the invention includes a microfabrication method for producing a the drug-delivery particles. The method generally includes the steps of (a) exposing a sheet of particle-forming material to a photoablating light source through a photomask, thereby forming a reticular lattice pattern on the sheet corresponding to the desired particle size and shape, and continuing this exposing until the desired particles are formed.
These are other objects and features of the invention will become apparent when the following detailed description of the invention is read in conjunction with the accompanying figures.